Webinar: Hairy Cell Leukemia (HCL) Clinical Trials
Comparing Vemurafenib+Obinutuzumab versus Cladribine+Rituximab
April 2025
This webinar was hosted by the Hairy Cell Leukemia Foundation (HCLF) with guest speaker Dr. Jae Park from Memorial Kettering Cancer Center. This presentation is part of HCLF’s clinical trials webinar series. Through this series, we aim to educate our patient network about current trials in Hairy Cell Leukemia and empower them with options.
View Dr. Park’s slides >>
View a recording of Dr. Park’s presentation below.
Transcript of Presentation from Dr. Jae Park
Thank you so much for the kind introduction. I've been very fortunate to be part of the Hairy Cell Leukemia Foundation for many years who have been great partners in providing fantastic education and resources for our patients and supporting several research projects.
So, today I'll be talking about and highlighting one particular clinical trial that we are currently running that's also supported by the Hairy Cell Leukemia Foundation in conjunction with the Leukemia Lymphoma Society. I'll provide some background, providing rationale of why we are doing such studies. Even though today's talk is focused on newly diagnosed patients, I'll be talking about recurrent or relapsed Hairy Cell Leukemia patients, which is where it started first. And now we're moving this therapy to the newly diagnosed setting.
I'm from Memorial Sloan Kettering Cancer Center in New York City. I'm one of the leukemia physicians treating Hairy Cell Leukemia at our center.
What is Hairy Cell Leukemia?
So, to set the ground to talk about what Hairy Cell Leukemia. The cells, when you look under the microscope, they have these hairy-like the projections here. Hence the name Hairy Cell Leukemia.
It is a type of a chronic B cell lympho proliferative blood cancer. It just simply means that, our bone marrow (these are bone marrow-based diseases) starts to make these abnormal B cells as hairy cells.
So, it is a rare disease. It is estimated to be about 600 to 800 new cases per year in the United States. Compared to 300,000 new cases that we see of the breast cancers and so forth, this is an extremely rare disease. Although I have to say that we are seeing increasing incidence, through the awareness of the foundation and being tested.
The key clinical features and how the patients typically do present to the clinic. One is enlarged spleen. The second is the abnormal blood counts, which are probably the most common way of presenting. And it can come up with many different clinical situations. One is anemia, which simply means low hemoglobin. The second is thrombocytopenia, which means low platelet cell count. And then neutropenia, which means low absolute neutrophil count, or low neutrophil count, which implicates increasing infectious risk.
The third finding is bone marrow fibrosis, which, may not be appreciated as much. When we do a bone marrow biopsy, often times leukemia patients have a fibrotic marrow. And this is typically found when we do a bone marrow aspirate.
You may have heard that we have a dry tap; we're not able to get the flow or the good samples. And that's often because it has a fibrotic marrow, so we don't get a lot of fluid when we do the bone marrow aspirates.
Presence of BRAF V600-E mutation
Lastly, which is highly relevant is the Hairy Cell Leukemia carries this BRAF V600-E mutation in more than 90%. Almost always this mutation is present for classical Hairy Cell Leukemia patients. The BRAF itself is not unique to Hairy cell. The same mutation is present in many other cancers, including many solid tumors such as melanoma and other blood cancers too.
But what is unique is almost all Hairy Cell Leukemia carries this mutation, which means that the mutation itself is a critical component for Hairy Cell Leukemia survival. So, by targeting that specific mutation that we might be able to get a deeper response.
We'll get to that and then how we have developed the BRAF targeted approach.
Standard chemotherapy-based treatment
Before we get there, we'll talk a little bit about the clinical background of what you may consider to be as the standard Hairy Cell Leukemia treatment.
For newly diagnosed patients for over 20 years, the standard therapy has been either Cladribine or pentostatin. This is a type of intravenous chemotherapy in the category of a purine analog, and that's a class of chemotherapeutic agents. Either Cladribine or pentostatin alone could result in about 60 to 80% of the time complete remission, and 10 to 20% of the time partial remission.
Complete remission refers to complete normalization of the blood counts and the reduction of the spleen to a normal size, plus the absence of a Hairy Cell in bone marrow. And partial response means everything in the complete remission, meaning the normal blood counts, normal spleen size, but when we do a bone marrow biopsy then we still do see some Hairy Cell Leukemia, so hence the partial remission.
So, if you don't do a bone marrow biopsy, we really can't say whether it's complete or partial. We just simply use the word clinical remission, which means the normalization of the blood count and the reduction of spleen size.
So, these numbers are fantastic results. So, you know, for those who have had other blood cancers or family members or friends with other blood cancer, these numbers are really a fantastic result from the single agent.
However, we don't consider the Cladribine or pentostatin alone to be a cure. About 30% of the patients will experience recurrent disease after receiving Cladribine or pentostatin, and we believe they do have a recurrence of disease because by itself, while they're great at restoring normal blood counts, they never really get rid of the Hairy Cell Leukemia completely from the bone marrow.
Those are called measurable residual disease or MRD. So almost all cases will be MRD positive if we use Cladribine or pentostatin alone, and those remaining cells in 30% of the time will eventually grow and lead to recurrence, dropping of the blood counts and enlargement of the spleen. Again, very similar to the initial clinical presentation and needing a second therapy.
Combining Cladribine with Rituximab
Now, another approach is what about if we add Rituximab, which is an anti-CD 20 targeted antibody, so it is a form of immunotherapy. It's an IV formulation. If you will add Cladribine plus Rituximab together that does improve complete remission rate and a reduced recurrence rate to about 5% or sometimes even less than that. So, it does get into a deeper remission and therefore less chance of recurrence.
And if we have time, we can talk about it, but it's a little bit beyond the scope of this clinical trial. The question is, Cladribine alone versus Cladribine plus Rituximab for newly diagnosed patients? Overall survival is the same meaning that you'll live just as long, whether you get Cladribine or Cladribine plus Rituximab, but your chance of a recurrence or needing a second or subsequent line of therapy will be lower If we get the Cladribine plus Rituximab the first time.
Limitations of chemotherapy-based treatment
Now these therapies are great, and you may argue that we might have solved all the problems in Hairy Cell Leukemia with this chemotherapy and Rituximab combination. So, what is the problem? So, these chemotherapies as you may imagine, are associated with immune suppressions.
So, what that means is that once you get the chemo, your blood count may start here and they will dip down and hit lowest blood counts within a few weeks of the chemotherapy, and they will eventually recover. But during that low time, neutropenic time or thrombocytopenic time, the infectious risk is high. So, the estimated rate of a neutropenic fever, meaning having fever or infection while your blood count is low, the neutropenia, is about 40%. And that does mean hospitalizations, whether it's a few days, two or three days of hospitalizations, or seven to 10 days. About 40% of the time that it is likely to happen.
And obviously that does depend on what the blood counts are when you start. So, there's a caveat to that. But that is estimated in the clinical trial reports. So those are the biggest side effects associated with the chemotherapy. And depending on the number that you're starting with because there is a dipping down or lowering of the normal blood counts, you may require more blood and platelet transfusions after the chemotherapy.
This makes it harder for those patients who present with very low blood counts and have concomitant or concurrent infections and they need to be treated. And that does present the conundrum or the problem as to giving chemotherapy when they're already sick to begin with, and we're making them feel worse in order to make them feel better in the long term. But during the short term, there will be a more increased risk of complications.
Then lastly, the chemotherapy itself can cause second cancer, although those are rare events, but it can happen with any chemotherapy, certainly with a Cladribine or pentostatin. So, we saw the limitation of the Cladribine first, and then also, as I mentioned before, about 30% of the time with the Cladribine alone, the Hairy Cell Leukemia can happen again, and when it happens again, they can get the chemotherapy again. And most of the patients do respond. But there is subset of the patients who get second or third time with the Cladribine or pentostatin and they stop responding or they don't respond as long, and then they only get one year of a remission, and then the hairy cell leukemia comes back. So, we wanted to develop a therapy that we can we use in those patients who are either looking to avoid more chemotherapy or patients who are refractory or no longer responding to chemotherapy.
And because we knew that BRAF mutations were present more than 90% of the time, we figured that it must be important if it is happening so often in Hairy Cell Leukemia. It has to be an important mutation for the Hairy Cell Leukemia to survive.
Enrico Tiacci and Bruno Falini from Italy made a first discovery that the BRAF mutation was present in Hairy Cell Leukemia in 2011 in publication. And shortly thereafter, many other centers including ours, are validating.
And this table just summarizes that in subsequent publications, close to 500 patients that we validated and confirmed the presence of this mutation the BRAF mutation with Hairy Cell Leukemia. And what was also unique is that when the Hairy Cell Leukemia recurs after the initial therapy, the BRAF mutation continues to present. Which is an important factor for when we are designing a therapy for recurrent or relapse disease because the mutation may happen at the beginning, but they may disappear.
But these are consistent or persistent mutation in Hairy Cell Leukemia. So that does present a very good rationale for targeting this mutation in Hairy Cell Leukemia.
And then with some of the data that we also did at MSK, we looked at the Hairy Cell Leukemia initiating cells. So, the parent cells and the BRAF mutation were also present. Which made us think that, if we ever get closer to the hope of curing Hairy Cell Leukemia, we need to get that first cell that initiated Hairy Cell Leukemia. And if that cell contains the BRAF mutation, by targeting the mutation, we might be able to get one step closer to a cure.
The BRAF mutation is present in other cancers, and it's also present in melanoma. And they have already developed BRAF inhibitor or targeted medication called Vemurafenib for melanoma; it is already FDA approved.
Initial clinical trial using Vemurafenib alone
So, we wanted to use that. We conducted a clinical trial both in Italy and MSK; it was a multicenter US study with several investigators giving Vemurafenib, this oral BRAF inhibitor, alone for patients with relapsed disease.
The eligible patients or included patients for this clinical study were all relapsed or recurrent disease patients. Either they never responded to Cladribine, which is rare, or they responded but they had a recurrent disease. But they needed to have more than two relapses, meaning they had to have another Cladribine the second time and that didn't work, or it only lasted a very short time and for the third time and they needed a therapy, and they could get on to study.
This again, is a recurrent or refractory Hairy Cell Leukemia patients. And in order to participate in this study, and that's true for most of other Hairy Cell Leukemia studies, you need to have some evidence of a clinically significant disease, which means lower absolute neutrophil count, low hemoglobin, and then low platelet counts, one of those. And the Vemurafenib alone, when we were initially designing the study, we also weren't quite sure how long the therapy should be given. In melanoma because it's studied in metastatic disease, Vemurafenib was given indefinitely until the drug stops working.
So that could be a few months for some patients, that could be a few years for the other patients. But we didn't want to give the drug for too long. So, we designed the study to give the medications for three months. First, we did a bone marrow biopsy, and depending on their response, we could extend the drug duration for up to six months. So max of six months, minimum three months was the drug duration.
We used the same dose that were used for melanoma, which was 960 milligrams twice daily. We just simply adopted that same dose of medication that we use in melanoma for Hairy Cell Leukemia patients.
We treated 24 in US and then another 25 patients in Italy. So, the combined is about 45 to 50 patients together, and they have a similar result. And this is only the US data, but in out of the 24, they actually responded a hundred percent of the time. So, all patients who received the pill alone instead of the repeated course of the Cladribinee or pentostatin, responded.
So, when we look at the response, about 42% of the patients were complete response. And the other 58 or 60% were partial response. So, everybody had a normalization of the blood counts. But when we did the bone marrow biopsy, about 60% of the time we're still able to find Hairy Cell Leukemia.
And out of those 60%, some of those patients had a recurrent disease, which is what the survival curve is to show, meaning that initially, even though everybody responded, a subset of those patients had a recurrent or relapse disease when they received the Vemurafenib alone, by itself.
The second point I want to highlight is that the drug worked effectively and incredibly well, and because of a relatively less toxic medication, we're able to use the drug for older patients or sicker patients. So median age, about half the patients were older than 62. And then the oldest patient that were treated on this trial was 80 years old.
So again, and because the mechanism of action side effects is very different than chemotherapy, we were able to use the medications for older patients as well.
Common side effects of Vemurafenib
So, the drug did have its own side effects, which we knew going in because the drug already was FDA approved. So, there's already existing experience with melanoma patients.
Rash and joint pains are the two most common side effects I usually discuss with the patients. And the third and fourth are hair thinning and sunburns; photosensitivity could be quite significant too. So these grade one and two and grade three; it is a medical term that we use to indicate the severity of these side effects. Obviously the lower the grade the less likely, so the grade one and two the rash and joint pains are typically ones you will notice. That's easily managed either with Tylenol or Motrin; you may not even need any medications or pain medications to function. Grade three and higher are the ones a bit more significant, meaning that, they may need steroid or creams and other things to mitigate them.
So even though a good number of patients experienced rash and joint pains, the most of which were low grade, these are transient, reversible side effects that happen within the first two or three weeks of a starting therapy and they do disappear. You are able to stay on the medication to complete the therapy.
So, it's a more of an inconvenience factor than anything else with the side effects.
It worked very well, almost always, but it never got rid of the Hairy Cell Leukemia completely from the bone marrow.
Combining Vemurafenib with Rituximab
So, the next question that we asked is what about if we add Rituximab? Can we get a deeper or better response and reduce the chance of recurrence after using Vemurafenib plus Rituximab. We had already done this with Cladribine plus Rituximab, so chemo plus Rituximab.
I told you at the very beginning that when you added the Rituximab, which is CD 20 targeted immunotherapy, that we're able to get a better response and deeper response. So, we are taking a similar rational approach now, adding it to Vemurafenib, and this is a completely chemotherapy-free regimen. This is the data that Enrico from Italy published in 2021.
And again, this is recurrent refractory patients who have failed or have already been treated with a chemotherapy such as Cladribine or pentostatin. In this study, they use the same dose of Vemurafenib, 960 milligrams twice daily for eight weeks, so two months. And then the Rituximab was given every two weeks for eight doses with a total duration of a therapy of 18 weeks.
About 87% of the patients had a complete response. And what was different than the prior Vemurafenib alone or monotherapy, was that 90% of the response were MRD negative, which means that when we did the bone marrow biopsy, 27 out of 30 treated patients were not able to find any Hairy Cell Leukemia.
So that means that these patients are less likely to relapse because we wiped out the disease more completely. So, that was encouraging, even though it's a relatively shorter follow-up. These are MRD-free survival, meaning that those patients who got MRD negative, really nobody has been relapsing, at least for the duration of the follow up they had, which is about 30 months of a follow up.
So, this was highly encouraging that when you add the Rituximab, you get a deeper response, better response, reduce the chance of recurrence.
Introducing Vemurafenib + CD20 antibodies to newly diagnosed patients
So, the next question, then we ask, it works so well in recurrent disease, and can we take it to newly diagnosed patients? So instead of the chemotherapy-based regimen, can we use the same approach instead of a chemotherapy, not after failing chemo, but what about instead of the chemotherapy?
It was considered to be a bold step because, and I told you at the very beginning, most of our patients do very well with a chemotherapy-based regimen, but it has its own side effects. Not everybody is able to get it. If you're older or sicker or have an infection or very low blood counts, it usually is not safe to give a chemotherapy.
So at least for those subsets and for those other patients who are simply looking to alternative treatments, non-chemotherapy options, we wanted to develop this therapy for them in the frontline setting, not after failing chemotherapy.
I told you the BRAF mutation is happening in early hairy cell initiating cells. So, we wanted to see whether we can cure Hairy Cell Leukemia. It is considered to be incurable at this moment as a chronic disease, but can we cure this disease with a better therapy?
So, in order to do that, we wanted to use the BRAF inhibitor Vemurafenib that has been tried multiple times in different clinical trials in Hairy Cell Leukemia. And instead of Rituximab, we swapped that with what's called Obinutuzumab. It's a very same class of medications, but it's more potent. So, it's a little bit stronger. It works better than Rituximab. So, we wanted to, in the frontline setting, we wanted to give the best-in-class medications to hopefully get the best response with the deeper remission, with the goal of less relapse and eventually a cure.
This study was also supported by the Hairy Cell Leukemia Foundation with Vemurafenib Plus Obinutuzumab in now patients previously untreated. So, this is the first time that we ever studied this combination in the world, looking at chemotherapy-free regimen for newly diagnosed Hairy Cell Leukemia patients.
The duration that we have chosen with the same dose of Vemurafenib at 960 milligrams twice daily for four months continuously. We added Obinutuzumab from months two, so it started a month after, so for three months duration. And total of five doses of Obinutuzumab infusion. Three centers participated in the US for this study - MSK, Dana-Farber, and Yale. Again, median age was 54, meaning half the patients were younger than 54. Half the patients older than 54. So youngest patient you can see is a 28-year-old. And I think avoiding chemotherapy makes even more sense for younger patients, in my opinion, because they do live longer and they like to avoid long-term consequences of the chemotherapy, but also certainly it makes sense for older patients. And the oldest patients we treated on this study was 82-year-old.
So, with this combination that we had about 90% response rate to 27 out of 30 patients. The other 33 patients who dropped out of the study early within the first month or so, the patients who did get those side effects I mentioned before, rash and joint pains and did not want to continue. But those patients who continued the therapy to 27 and complete them all patients, a hundred percent of those patients responded.
And I told you about this MRD negativity, meaning when we do the bone marrow biopsy, what is the chance of that we don't see any Hairy Cell Leukemia, that was happening in 96%. So, this graph on the right is showing this dramatic decrease for Hairy Cell Leukemia percentages in the bone marrow, pre-treatment and after treatment; all patients Hairy Cell Leukemia disappeared. At the beginning, there's a variable presence of BRAF mutation and all disappeared after. So, this is again, just another indicator of the complete and the rapid eradication of the Hairy Cell Leukemia with this chemotherapy-free combination approach.
And because it's chemotherapy-free and doesn't have the lowering of the blood counts at the beginning because it doesn't impact the normal red and platelet and normal neutrophils, we were able to initiate in outpatient in all patients, except two. Two patients did start the therapy with concomitant infection which chemotherapy would've been hard. But we wanted to test the hypothesis that we can safely administer this treatment in patients who actually had a fever and infections and other things. So, with those patients, we did treat them, but in the hospital. They have completed the therapy and also responded as well safely.
I wanted to highlight the speed of the blood count recovery. I told you with the chemotherapy, you start here and then there's always a dipping down or lowering down of the normal blood counts before they recover. Because this is chemotherapy-free regimen, if you look at the platelet counts, which is mostly exemplary, there's no kind of dipping down. So, from the very beginning of starting therapy, you can start from less than 100 and recover very fast within four weeks. Normal, without that kind of dipping low. So just to highlight the speed of a response.
And platelet is always the first blood count to recover. The second is a neutrophil, and even the neutrophil you can see is a steadier increase; there's no dipping down and going up. So, because of that, we reduced the chance of having the febrile episode while your blood count is low.
Lastly, I told you that almost everybody who finished the therapy responded. And how many of those patients have recurred and it's zero so far. So, no patients had a relapsed disease so far and the longest patient that we have treated is seven years out.
So, these are very encouraging. Obviously, we need a longer follow up because, you might have heard in the Hairy Cell Leukemia patients, recurrence can happen many years later, even 10 years later. So, while the seven years one may consider quite long for any other blood cancers, for Hairy Cell Leukemia we do want a little bit more time to see that this is validated and is true beyond the seven years and certainly beyond 10 years and 15 years.
We're going to continue to follow up these patients, but it is very encouraging nonetheless that no one has relapsed after their initial response so far in the newly diagnosed setting. So obviously we're very excited about this data.
It does have its own side effects and there are some lessons that we have learned from this too.
And it's the same side effects that we have seen in the relapse refractory setting. And the most common ones, the rash, arthralgia, which is the joint pain. And pruritus means just itching of the skin. So, these are still transient, reversible. They do go away once you stop the medications; the pain is manageable. In some cases, we do use low dose prednisone, like 10 to 20 milligrams, which is low dose for about four days or up to seven days. And that's enough to eradicate the symptoms.
But nonetheless, these are side effects that we do tend to manage. In contrast, the febrile neutropenia did happen, but in only in 7% of the patients as opposed to 40% of the time, which is estimated with a chemotherapy-based approach, which is dramatically lower.
The last lesson that we have learned is when patients do get the rash and joint pains, one of the things we do other than managing the symptoms is lowering the dose of Vemurafenib. When we designed the initial Vemurafenib study, we simply took the dose that was useful for melanoma patients, which is 960 milligrams twice daily, and just took the dose to Hairy Cell Leukemia patients.
But we have learned in melanoma, it doesn't work as well, and it is a completely different disease. The Hairy Cell Leukemia is very sensitive to Vemurafenib. So, the question was raised, do we even need this 960 milligram? Can we get away with a lower dose? So, in separate studies in Germany and other countries, they looked at doses as low as a 240 milligram twice daily, which is one pill twice a day. 960 is a four pill twice a day. So, with as low as 240 milligrams, it worked just as well. So, for side effects, one way to manage was a 400 milligram twice daily.
The half the dose was as good and actually almost everybody ended up in the half the dose for better management of the side effects. And so, in the future, this is a dose that I'm using off clinical trial for the better tolerability, same efficacy. And this is a dose that we're using in our future studies in a hope that we actually get even better in toxicity profiles.
Current clinical trial, comparing Vemurafenib + Obinutuzumab with Cladribine + Rituximab
So, I'm going to lead to my last slide highlighting the clinical trial that we are running currently, which is a phase two. Now this is the same regimen, Vemurafenib and Obinutuzumab same schedules. Only difference here is a dose of Vemurafenib.
This is a randomized study. So, half the patients will get this chemotherapy-free regimen. The other half will get what's considered to be the standard, which is Cladribine and Rituximab. This given weekly times eight. So, we're now comparing side by side to see which one is safer and better.
This is a multicenter study that is currently open and enrolling.
We have treated a few patients at MSK. It will open also at Ohio State and Dana-Farber. And this is again for newly diagnosed patients.
So, our main hypothesis here; we already know that both therapy works very well but they've never been compared side by side. So, what's happening in the real world right now is that you can certainly get Cladribine and Rituximab as a standard therapy. You might be able to get the BRAF and Obinutuzumab based on our prior data in the newly diagnosed setting. But the NCCN or cancer society guidelines have a restriction. It's only for older patients or patients who have a concurrent infection.
So, if you do not meet those criteria, insurance may not pay for that, even though that's not how our study was designed. That's the reality that insurance payers are only providing for those two indications. So, we wanted to compare definitively against the chemotherapy for appropriate patients, so can we expand the indication and then use the therapy for more patients if we believe it is appropriate.
So, our main hypothesis here is that the Vemurafenib and Obinutuzumab, the chemotherapy-free combination, will be just as effective as the Cladribine and Rituximab, but safer with less side effects, especially infections and hospitalizations. The rate of blood and platelet transfusions are the key side effect markers, which impact the quality of life, the time off from work and in the hospital. Sometimes we have to administer Cladribine in the hospital as well too. So, we're trying to reduce those complications and inconvenience factors.
And again, the goal and the primary purpose of this study is that we want to establish this chemotherapy-free regimen as appropriate first line therapy option for all patients, not just older patients, not just with a concurrent infection. So, it'll be easier eventually to administer or use this regimen for a wider group of patients. And randomized study in the medical field is the gold standard; it is the best way to convince the payers, clinicians and the patients' community oncologists who may actually see these patients more often to have a wider buy-in when you compare directly against chemotherapy effectiveness.
I believe fully that they will be just as good for both based on the single arm studies that we have conducted. But this clinical trial is really focusing on the safety of other factors. And there are many other scientific questions we'll be asking as a part of the study, and that's what the funding is also providing for.
So, lastly, I just wanted to thank you for your support and please do spread the word that if you belong to this category, have an interest in this. And other patients you might be speaking to. Consider participating in the trial. The quicker we finish this study, the quicker that we can get this combination to the patients.
This transcript has been edited for clarity.